The compounds according to the invention are inhibitors of cholesterol biosynthesis, in particular inhibitors of the enzyme 2,3-epoxysqualene-lanosterol cyclase, a key enzyme of cholesterol biosynthesis. The compounds according to the invention are suitable for the treatment and prophylaxis of hyperlipidaemias, hypercholesterolaemias and of atherosclerosis. Further possible applications include the treatment of hyperproliferative skin and vascular disorders, tumours, gallstone trouble and mycoses.
Compounds which intervene in cholesterol biosynthesis are important for the treatment of a number of syndromes. Particular mention may be made in this regard of hypercholesterolaemias and hyperlipidaemias, which are risk factors for the formation of atherosclerotic vascular changes and their sequelae such as, for example, coronary heart disease, cerebral ischaemia, intermittent claudication and gangrene.
The importance of excessive serum cholesterol levels as a main risk factor for the formation of atherosclerotic vascular changes is generally recognized. Extensive clinical studies have led to the realization that the risk of suffering from coronary heart diseases can be decreased by reduction of the serum cholesterol (Current Opinion in Lipidology 2(4), 234 [1991]). Since the largest part of the cholesterol in the body is self-synthesized and only a small part is absorbed from food, the inhibition of biosynthesis represents a particularly attractive route to lower increased cholesterol levels.
In addition, treatment of hyperproliferative skin and vascular disorders and of oncoses, the treatment and prophylaxis of gallstone trouble and use in mycoses are described as further possible applications for cholesterol biosynthesis inhibitors. In this connection, in the latter case, intervention in ergosterol biosynthesis in fungal organisms, proceeds to a large extent in a manner analogous to the intervention in cholesterol biosynthesis in mammalian cells.
Cholesterol or ergosterol biosynthesis proceeds, starting from acetic acid, via a relatively large number of reaction steps. This multistage process offers a number of possibilities for intervention, of which the following may be mentioned as examples:
.beta.-Lactones and .beta.-lactams having potential anti-hypercholesterolaemic action which inhibit the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) synthase have been described (see J. Antibiotics 40, 1356 [1987], U.S. Pat. No. 4,751,237, EP-A-0462667 and U.S. Pat. No. 4,983,597).
Inhibitors of the enzyme HMG-CoA reductase are 3,5-dihydroxycarboxylic acids of the mevinolin type and their .delta.-lactones, whose representatives lovastatin, simvastatin and pravastatin are used in the therapy of hypercholesterolaemias. Further possible applications of these compounds are in the treatment of fungal infections (U.S. Pat. No. 4,375,475, EP-A-0113881, U.S. Pat. No. 5,106,992), skin disorders (EP-A-0369263) and gallstone trouble and oncoses (U.S. Pat. No. 5,106,992; Lancet 339, 1154-1156 [1992]). The inhibition of smooth muscle cell proliferation by lovastatin is described in Cardiovasc. Drugs Ther. 5, Suppl. 3, 354 [1991].
The suitability of inhibitors of the enzyme squalene synthetase e.g. isoprenoid -(phosphinylmethyl)phosphonates, for the treatment of hypercholesterolaemias, gallstone trouble and oncoses is described in EP-A-0409181 and J. Med. Chemistry 34, 1912 [1991], and the cholesterol-lowering and antimycotic squalestatins are described in J. Antibiotics 45, 639-647 [1992] and J. Biol. Chemistry 267, 11705-11708 [1992].
As inhibitors of the enzyme squalene epoxidase are known allylamines, such as, naftifine and terbinafine which have found their way into therapy as agents against fungal disorders, as well as the allylamine NB-598 which has antihypocholesterolaemic action (J. Biol. Chemistry 265, 18075-18078, [1990]) and fluorosqualene derivatives which have hypercholesterolaemic action (U.S. Pat. No. 5,011,859). In addition, piperidines and azadecalins with potential hypocholesterolaemic and/or antifungal activity, whose mechanism of action is not unequivocally clarified and which are squalene epoxidase and/or 2,3-epoxysqualene-lanosterol cyclase inhibitors, have been described (EP-A-0420116, EP-A-0468434, U.S. Pat. No. 5,084,461 and EP-A-0468457).
Examples of inhibitors of the enzyme 2,3-epoxysqualene-lanosterol cyclase are diphenyl derivatives (EP-A-0464465), aminoalkoxybenzene derivatives (EP-A-0410359) and piperidine derivatives (J. Org. Chem. 57, 2794-2803 [1992]), which have antifungal activity. In addition, this enzyme is inhibited in mammalian cells by decalins, azadecalins and indane derivatives (WO 80/08450, J. Biol. Chemistry 254, 11258-11263 [1981], Biochem. Pharmacology 37, 1955-1964 [1988] and JP 64/003 144), and also by 2-aza-2,3-dihydrosqualene and 2,3-epiminosqualene (Biochem. Pharmacology 34, 2765-2777 [1985]), squalenoid epoxide vinyl ethers (J. Chem. Soc. Perkin Trans. I, 1988, 461) and 29-methylidene-2,3-oxidosqualene (J. Amer. Chem. Soc. 113, 9673-9674 [1991]).
Finally, as inhibitors of the enzyme lanosterol-14.alpha.-demethylase one may also mention steroid derivatives with potential antihyperlipaemic action and which simultaneously affect the enzyme HMG-CoA reductase (U.S. Pat. No. 5,041,432, J. Biol Chemistry 266, 20070-20078 [1991], U.S. Pat. No. 5,034,548). In addition, this enzyme is inhibited by the antimycotics of the azole type as represented by N-substituted imidazoles and triazoles. This class includes, for example, the commercially available antimycotics ketoconazole and fluconazole.
The compounds of the following general formula I are novel. Surprisingly it has been found that they are very effective inhibitors of the enzyme 2,3-epoxysqualene-lanosterol cyclase (International Classification: EC5.4.99.7).
The enzyme 2,3-epoxysqualene-lanosterol cyclase catalyzes a key step in cholesterol or ergosterol biosynthesis, namely the conversion of 2,3-epoxysqualene to lanosterol, the first compound with steroid structure in the biosynthetic cascade. Compared to inhibitors of earlier biosynthetic steps, such as, for example, HMG-CoA synthase and HMG-CoA reductase, the advantage of greater selectivity can be expected from inhibitors of this enzyme, since the inhibition of the earlier biosynthetic steps leads to the decrease of biosynthetically formed mevalonic acid and as a result can also adversely affect the biosynthesis of the mevalonic acid-dependent substances dolichol, ubiquinone and isopentenyl-t-RNA (cf. J. Biol. Chemistry 265, 18075-18078 [1990]).
In the case of inhibition of biosynthetic steps after the conversion of 2,3-epoxysqualene to lanosterol, there is the risk of the accumulation of intermediate products with steroid structure in the body and the triggering of the resultant toxic effects. This is described, for example, for triparanol, a desmosterol reductase inhibitor. This substance had to be withdrawn from the market because of the formation of cataracts, ichthyosis and alopecia (cited in J. Biol. Chemistry 265, 18075-18078 [1990]).
As already stated at the beginning, inhibitors of 2,3-epoxysqualene-lanosterol cyclase are occasionally described in the literature. The structures of these compounds, however, are completely different from the structure of the compounds according to the invention of the below-mentioned general formula I.
The invention relates to the provision of antihypercholesterolaemic substances which are suitable for the treatment and prophylaxis of atherosclerosis and which, in contrast to known active compounds, are distinguished by a better antihypercholesterolaemic action and have greater selectivity and thus greater safety. Since the compounds according to the invention can also inhibit ergosterol biosynthesis in fungal organisms on account of their high activity as inhibitors of the enzyme 2,3-epoxysqualene-lanosterol cyclase, they are also suitable for the treatment of mycoses.